We conducted a population-based matched cohort study to examine attributable costs of NTM-PD and NTM-PI from the healthcare payer perspective (Ontario Ministry of Health and Long-Term Care, Toronto, ON, Canada). Costs were identified by using provincial health administration data, including physician services, emergency department data, hospitalizations, prescription medications (for those >65 years of age), population data (e.g., census information and death records), and special collections (e.g., specific disease registries) (12). These data can be individually linked by using unique encoded identifiers at ICES (formerly the Institute for Clinical Evaluative Sciences), an independent, nonprofit research institute in Ontario, whose legal status under Ontario health information privacy law allows it to collect and analyze healthcare and demographic data without consent for health system evaluation and improvement (12). Descriptions of key ICES databases are described in more detail elsewhere (13–15). Our study was approved by the ethics review boards of Public Health Ontario and the University Health Network. All data analyses were conducted by using SAS version 9.4 (SAS Institute, https://www.sas.com).

We identified incident cases of NTM by using laboratory data from Public Health Ontario (https://www.publichealthontario.ca) for 2001–2012. NTM-PD was defined by the microbiological criteria of the American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) diagnostic guidelines: NTM isolation from >2 sputum samples (isolation of the same species within 2 years) or >1 positive sample from bronchoalveolar lavage or pleural fluid (5). NTM-PI was defined by NTM isolation from only 1 sputum sample. Persons were excluded if age, sex, or birth date data were not available; if they did not live in Ontario on the index date; if they were >100 years of age on the index date (i.e., the beginning of healthcare resource utilization related to NTM); if laboratory-confirmed M. gordonae had been isolated from them; or if laboratory-confirmed NTM had been isolated from them in the 3 years before the accrual period (January 1, 1998–December 31, 2000).

Because dates of disease onset were unknown, we adjusted index dates by using joinpoint (https://surveillance.cancer.gov/joinpoint) analysis on the cost curve (where a change in costs indicates change in healthcare use) and clinical judgement to estimate an onset of 30 days before laboratory confirmation of NTM. In the 30 days before laboratory confirmation, clinical judgement reconciled the increasing costs with the expectation of physician visits, possible hospitalizations, and a large number of clinical investigations.

Matched unexposed persons (who never had NTM-PD or NTM-PI) were drawn from the general population in the Registered Persons Database (https://datadictionary.ices.on.ca/Applications/DataDictionary/Library.aspx?Library=RPDB). We matched unexposed and exposed persons at a ratio of 3:1 by using a combination of hard-matching and propensity score matching without replacement (Tables 1, 2). We used a logistic regression model that regressed exposure status to calculate the propensity score based on the following covariates: rurality (using the Rurality Index of Ontario [16]), neighborhood income quintile, and underlying conditions 2 years before index date (using the Johns Hopkins Adjusted Clinical Groups System [17]). Persons were hard-matched by age, sex, and index date as well as within 0.2 SDs of the logit of the propensity score (18). To examine the effect of NTM-PD and NTM-PI on costs before death, we rematched each exposed person who died during the observation period (2001–2012) with 3 unexposed persons from the general population who also died during the same period, by using covariates assessed 180 days before death (Table 1).

We evaluated deaths (10-day, 30-day, 90-day, 1-year), acute hospital admissions (within 5 and 30 days of index date), and hospital lengths of stay. We calculated costs by using person-level costing methods established by ICES (14). This method uses administrative data to calculate long-term costs of incident cases from an index date to a defined point in time (death or the end of an observation window). In this method, costs are inflated by using the healthcare-specific Consumer Price Index reported by Statistics Canada (14). The publicly funded healthcare service categories included were acute inpatient hospitalizations, emergency visits, same-day surgeries and other ambulatory treatments, inpatient rehabilitation, complex continuing care, long-term care, inpatient mental health, physician services, home care, eligible prescription medications, and devices (14).

We calculated all costs in 2015 Canadian dollars (CAD) and present results in 2018 CAD and US dollars (USD). Costs were inflated from 2015 CAD by using the healthcare-specific Consumer Price Index (19) and converted to 2018 USD (1 CAD = 0.77 USD) (20). Using phase-of-care methods, we estimated NTM-PD– and NTM-PI–attributable healthcare costs for acute and long-term illness. We defined 3 phases (acute, continuing, and subsequent) by using joinpoint analysis (21) and clinical judgment. Clinical judgment supported the results of joinpoint analysis with consideration of typical patterns of physician visits, clinical investigations, treatment initiation, and illness duration. We divided the acute care (phase 1) into 2 parts: initial and subsequent. The remaining phases were continuing care (phase 2) and before death (phase 3). Phase 1 was estimated to last 150 days from the index date; the first 60 days were defined as initial care and the remaining 90 days as subsequent care. Phase 2 started 70 days before death. Observation time was divided into phases in order of final, initial, and subsequent care; the remaining observation time was allocated to continuing care. For example, if a person was observed for 400 days, the last 70 days were assigned to the before-death phase and the first 150 days to initial (60 days) and subsequent (90 days) care, cumulatively representing phase 1; the remaining 180 days were allocated to the continuing care phase.

We calculated phase-specific attributable costs as the mean difference between matched pairs, and we used bootstrapping to calculate the 95% CI of the mean difference (22). Costs were measured as 10-day intervals throughout the observation period. We also considered attributable costs by persons’ age category, sex, and healthcare spending category. We determined attributable mean 1-year costs by applying 10-day survival probabilities from the first year after diagnosis to the mean 10-day phase-specific costs as we described.

We conducted a sensitivity analysis by removing persons identified in the Ontario Cancer Registry (https://datadictionary.ices.on.ca/Applications/DataDictionary/Library.aspx?Library=OCR) and the Canadian Cystic Fibrosis Data Registry (https://datadictionary.ices.on.ca/Applications/DataDictionary/Library.aspx?Library=CFDR) as having any history of lung cancer or cystic fibrosis because of possible differences in expected complications and costs associated with these conditions. We performed cost analysis for the matched cohort without these persons and by using the same methods we described.

During 2001–2012, a total of 7,384 NTM-PD cases and 8,580 NTM-PI cases were identified and linked to administrative data (Table 3). The mean (± SD) age of NTM-PD patients was 66.1 (± 15.6) years and of NTM-PI patients was 61.1 (± 18.3) years. Of the NTM-PD patients, 3,732 (50.5%) were female, 316 (4.3%) lived in rural areas, and the mean collapsed aggregated diagnosis groups score was 5.5 (± 2.1). Of the NTM-PI patients, 4,158 (48.5%) were female, 285 (3.3%) lived in rural areas, and the mean collapsed aggregated diagnosis groups score was 5.1 (± 2.2).

Of the NTM-PD patients, 272 (3.7%) were admitted to a hospital within 5 days of the index date and 3,839 (52.0%) were admitted within 30 days. The mean (± SD) length of hospital stay was 11.1 (± 20.5) days for those admitted within 5 days and 10.7 (± 24.0) days for those admitted within 30 days. For these patients, the 90-day all-cause mortality rate was 6.0% (n = 444) and the 1-year rate was 13.9% (n = 1,024).

Of the NTM-PI patients, 241 (2.8%) were admitted to the hospital within 5 days and 2,294 (26.7%) within 30 days; mean (± SD) length of stay was 10.6 (± 22.9) days for those admitted within 5 days and 14.0 (28.5) days for those admitted within 30 days. For these patients, the 90-day all-cause mortality rate was 3.4% (n = 294) and the 1-year rate was 8.6% (n = 738).

We matched 7,243 (98.1%) of NTM-PD and 8,393 (97.8%) of NTM-PI patients to unexposed persons. All standardized differences were <0.1, indicating good balance (Table 2). We matched 3,116 (98.8%) of NTM-PD and 2,616 (97.8%) of NTM-PI patients who died and found that standardized differences were <0.1 for both groups.

For NTM-PD and NTM-PI, the mean attributable costs over the first 3 phases declined to the lowest cost during the continuous care phase (CAD $236 [USD $182], 95% CI CAD $199–$272 [USD $154–$210] for NTM-PD; CAD $133 [USD $103], 95% CI CAD $111–$154 [USD $85–$119] for NTM-PI). Costs then increased to the highest costs in the before-death phase (CAD $1,352 [USD $1,044], 95% CI CAD $1,104–$1,601 [USD $852–$1,236] for NTM-PD; CAD $731 [USD $565], 95% CI $506–$958 [USD $390–$739] for NTM-PI) (Table 4). For NTM-PD and NTM-PI, hospitalizations accounted for the largest proportion of costs across all phases. In the initial infection phase, 67.9% (CAD $663 [USD $512]) of NTM-PD costs and 65.5% (CAD $415 [USD $320]) of NTM-PI costs were for hospitalization.

For NTM-PD and NTM-PI patients, mean attributable hospitalization costs were highest before death (NTM-PD CAD $1,265 [USD $976], 95% CI CAD $1,033–$1,498 [USD $797–$1,156]; NTM-PI CAD $737 [USD $569], 95% CI CAD $524–$949 [USD $404–$732]) and second highest during the initial infection phase (NTM-PD CAD $663 [USD $512], 95% CI CAD $603–$723 [USD $465–$558]; NTM-PI CAD $415 [USD $321], 95% CI CAD $382–$450 [USD $294–$347]). Physician service costs were greatest during the initial infection stage, costing an average of CAD $187 (USD $144), 95% CI CAD $177–$196 (USD $137–$151) more than uninfected persons for NTM-PD and CAD $119 (USD $92), 95% CI CAD $114–$125 (USD $88–$97) more than uninfected persons for NTM-PI.

For NTM-PD patients, costs were greatest during the before-death phase and the initial infection phase (Figure 1). The highest costs before death were found for patients in the <25 years age group (CAD $7,952 [USD $6,138], 95% CI CAD $3,840–$19,744 [USD –$2,963 to $15,238]; n= 7) and declined in each subsequent age group; the lowest costs before death were found for patients >85 years of age (CAD $762 [USD $588], 95% CI CAD $379–$1,145 [USD $293–$883]; n = 778). Similarly, the highest costs before death for NTM-PI patients were for those <25 years of age (CAD $16,303 [USD $12,583], 95% CI CAD $16,161–$16,446 [USD $12,473–$12,692], n<6); however, the lowest attributable costs were for those 25–44 years of age (CAD $261 [USD $202], 95% CI CAD –$2,519 to $3,041 [USD –$1,944 to $2,347]; n = 57), followed by declining costs in each of the subsequent age categories: 45–64 years (n = 351), 65–84 years (n = 1,440), and >85 years (n = 822) (Figure 2).

Overall, mean attributable costs were higher for male than for female NTM-PD patients in all phases except before death, when attributable costs were higher for female than male patients (Figure 3). In the before-death phase, NTM-PD female and male attributable costs were CAD $1,316 (USD $1,016), 95% CI CAD $925–$1,709 (USD $714–$1,319) for female patients and CAD $1,166 (USD $900), 95% CI CAD $826–$1,505 (USD $638–$1,162) for male patients. For NTM-PI patients during all phases, mean attributable costs were higher for male than for female patients (Figure 4). The mean attributable cumulative 1-year costs adjusted for survival were CAD $14,953 (USD $11,541) per NTM-PD patient and $CAD 8,729 (USD $6,737) per NTM-PI patient.

After removing from analysis persons with a history of lung cancer or cystic fibrosis, we matched 6,461 NTM-PD and 7,887 NTM-PI patients to unexposed persons. For NTM-PD, total mean attributable 10-day costs per patient were CAD $951 (USD $734), 95% CI CAD $875–$1,027 (USD $675–$792) for initial infection; CAD $428 (USD $330), 95% CI CAD $370–$485 (USD $286–$374) for subsequent care; CAD $190 (USD $146), 95% CI CAD $153–$227 (USD $118–$175) for continuous care; and CAD $1,479 (USD $1,141), 95% CI CAD $1,176–$1,780 (USD $908–$1,374) for before-death phases (Table 5). For the same phases, the total mean attributable costs for NTM-PI patients were CAD $614 (USD $474), 95% CI CAD $570–$659 (USD $440–$508); CAD $220 (USD $170), 95% CI CAD $189–$253 (USD $146–$195); CAD $108 (USD $83), 95% CI CAD $85–$130 (USD $66–$100); and CAD $850 (USD $656), 95% CI CAD $589–$1,110 (USD $455–$857). For NTM-PD patients, the attributable costs in the sensitivity analysis were significantly lower during the subsequent care and continuous care phases. For NTM-PI patients, the costs were significantly lower during the continuous care phase only.